Inhibitors thermolysin

DePriest SA, Mayer D, Naylor CB, Marshall GR. 3D-QSAR of angiotensinconverting enzyme and thermolysin inhibitors a comparison of CoMFA models based on deduced and experimentally determined active site geometries. J Am Chem Soc 1993 115 5372-84. 

Klebe, G., Mietzner, T., and Weber, F. Different approaches toward an automatic structural alignment of dmg molecules applications to sterol mimics, thrombin and thermolysin inhibitors./. Comput.-Aided Mol. Des. 1994, 8, 751-778. 

Protease 3D structural models thermolysin-inhibitor complex ACE inhibitor drug design... 

The Mitsunobu phosphonate coupling has been adapted to the solid-phase synthesis of peptidyl phosphonates as well.1 2 In this environment, with excess phosphonate, even the more hindered, p-branched esters are formed efficiently. A series of phosphonate tripeptides have been synthesized and used to identify novel thermolysin inhibitors from a small library. (A number of other solid-phase syntheses of phosphonamidate-, 831 phosphonate-, 79 84 and phosphinate-peptides185,86 have been described however, in these instances the phosphorus bond forming steps were performed in solution, prior to solid-phase coupling.)... 

If the desired hydroxamic acids are sufficiently hydrophobic, workup is easily carried out using extraction and flash chromatography. However, many hydroxamic acids are soluble in polar solvents, which causes problems during isolation and purification. The structure of hydroxamic acid thermolysin inhibitors can be made more potent by the introduction of a malonyl moiety to match the specificity of thermolysin (Scheme 3). For example, in the synthesis of HONHCOCH(Bzl)CO-L-Ala-Gly-NH2 (4), O-benzylhydroxylamine was employed in the synthetic scheme to facilitate the isolation and purification of the intermediate 2.[101 The final precursor is a benzyl-protected hydroxamate 3 that can be deprotected by hydrogenolysis without byproducts contaminating the desired hydroxamic acid 4. 

De Priest, S. A., et al. 3D-QSAR of Angiotensin-Converting Enzyme and Thermolysin Inhibitors A Comparison of CoMFA Models Based on Deduced and Experimentally Determined Active-Site Geometries,/. Am. Chem. Soe. 

Wasserman and Hodge (290) used molecular dynamics to dock thermolysin inhibitors to an approximate model of the enzyme, with flexibility in the active site (3 8 of 314 residues) and ligand and with the rest of the enzyme represented by a grid approximation. A solvation model was used to compensate for desolvation in complex formation. To get 22 of 25 runs to orient the hydroxamate function correctly, the hydroxamate oxygens of the starting conformation were initialized within 4 A of the zinc. If they were allowed to vary to 8 A, then only 3 of 24 runs placed the ligand correctly. Obviously, there is a serious sampling problem. 

Klebe, G., Mietzner, T. and Weber, F. (1994b). Different Approaches toward an Automatic Alignment of Drug Molecules Application to Sterol Mimics, Thrombin and Thermolysin Inhibitors. J. Comput.Aid.Molec.Des., 8,751-778. 

Waller, C.L. and Marshall, G.R. (1993). Three Dimensional Quantitative Structure-Activity Relationship of Angiotesin Converting Enzyme and Thermolysin Inhibitors. 2. A Comparison of CoMFA Models Incorporating Molecular Orbital Fields and Desolvation Free Energies Based on Active Analog and Complementary Receptor Field Alignment Rules. JMeeLChem., 36,2390-2403. 

The structure of thermolysin-inhibitor complexes has shown the presence of a deep PI specificity pocket and the details of hydrogen bonding between enzyme and inhibitor [28]. Side-chain atoms of the enzyme are involved in interaction with the inhibitor amides and the inhibitor conformation is such that the subsites PI and P2 both point into the enzyme core (Rg-9). 

Figure 9. Thermolysin-inhibitor complex - an example of inhibitors bound to zinc endoproteases with the long spacer consensus. A stereo view of the active site site of thermolysin showing details of enzyme-inhibitor 2 interactions (Brookhaven Databank Code 5TLN). Enzyme side chains involved in inhibitor recognition are shown in magenta. The color code is as given for Fig. 6.

Nice isosteric variations were observed in a series of thermolysin inhibitors. For these isosteres the replacement of the phosphonamide (X = NH) function by a phos-phonate (X = O) or a phosphinate (X = CH2) fnnction demonstrated clearly that the maximal activity was associated with the phosphonamide which is able to establish a hydrogen bond with alanine 113 (Figure 15.6). 

Wong and McCammon (120) described the calculation of the free-energy difference of binding benzamidine versus para-fluorobenzamidine to trypsin, while Bash et al. (121) reported calculations on free energy of binding differences for several thermolysin inhibitors and for a single thermolysin inhibitor to different mutant thermolysins. Merz and Kollman (122) recently... 

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